The present invention relates to sustained-release pharmaceutical preparations and the method for making them. More particularly, it relates to a granular, water-soluble drug, such as aspirin, coated with a dual wall structure to give a delayed and sustained drug delivery. The dual walled coated drug may be mixed with uncoated drug and/or single walled coated drug to provide an improved sustained-release system.
As is well known, the maximum time of effectiveness in many pharmaceutical preparations, particularly those containing a water soluble drug such as aspirin, is only a few hours because of biological modification and/or elimination of the medication in the body. Consequently, repeated dosages must be taken at frequent intervals to obtain long term pain relief. Furthermore, aspirin usually dissolves readily in the gastric juices of the stomach and the total dosage is immediately fed into the blood stream. The level of aspirin in the blood stream constantly decreases because of the biological elimination, so there is little or no pain relief at the end of the period between dosages. As a result, the pain relief fluctuates between dosages corresponding to the peaks and valleys in the level of aspirin in the blood.
Many attempts have been made to develop timed-released pharmaceutical preparations which provide a more constant level of the drug in the blood over several hours.
One common approach is to microencapsulate aspirin, for example, with a capsule wall material which provides a slower dissolution rate than free aspirin. The early work in that regard is represented by U.S. Pat. Nos. 3,155,590; 3,341,416; 3,488,418, and 3,531,418. Those patents, among others, disclose dispersing particles of aspirin in a hot cyclohexane solution containing ethyl cellulose and then introducing a phase-separation inducing agent, such as butyl rubber or polyethylene. Upon cooling, the aspirin particles become coated with ethyl cellulose. The coated particles are then admixed with tabletting excipients and formed into dosage-sized tablets. When ingested, the tablets disintegrate rapidly and the individual particles of encapsulated aspirin are dispersed in the stomach. The gastric juices slowly diffuse through the capsule walls, dissolve the aspirin, and the dissolved aspirin slowly diffuses or leaches out through the capsule walls into the body. Although the resultant blood level content is sustained to a measurable extent, the aspirin is diffused into the body rapidly enough so there is an initially high bllod level content which decreases quite rapidly within a few hours. These dissolution properties yield undesirable blood aspirin concentration versus time curves.
In the first place, the time required to reach therapeutic levels after ingestion is longer for timed-release aspirin than for free aspirin. For this reason, it has been proposed that free aspirin be tableted with coated aspirin particles,. See, for example, U.S. Pat. No. 3,115,441 which discloses mixing aspirin particles having a series of coatings thereon with uncoated aspirin, and tableting so that the coated particles are entrapped in uncoated aspirin. Tablets made according to the method have the advantage of providing immediate relief because the free aspirin (which comprises the initial dosage) dissolves immediately upon ingestion. However, as with the other preparations discussed above, the tablet rapidly disintegrates in the stomach.
See also Guy U.S. Pat. No. 4,025,613 where a multi-layered tablet is disclosed. One layer comprises aspirin coated with cellulose acetate phthalate and the other layer is free aspirin. However, as stated in Dunn, U.S. Pat. No. 4,520,009, while aspirin tablets prepared by the process of Guy exhibit desirable in vitro release properties, processing difficulties are encountered in production runs. Dunn, then, is said to be an improvement in that large batch processing is allegedly made easier. In Dunn an admixture of aspirin, microcrystalline cellulose, cellulose acetate phthalate, plasticizer, corn starch and lubricant is compressed into tablet form. There is no microencapsulation as such in Dunn and, accordingly, the advantages of microencapsulated particles are foregone in favor of processing ease.
With microencapsulated particles, as discussed above, the dissolution rate decreases rapidly and the blood aspirin concentration at 2-3 hours must greatly exceed the therapeutic level in order to maintain adequate aspirin concentrations at 8 hours. As a result, efforts have been made to adjust the rate of dissolution and, thus, control the timing of sustained drug release. See, for example, Peters U.S. Pat. No. 3,492,397 where the dissolution rate is said to be controlled by adjusting the wax/ethyl cellulose ratio of the applied spray coating. See also U.S. Pat. Nos. 4,205,060 and 3,488,418 where it is indicated that the rate of dissolution can be controlled by varying the thickness of the coating.
Another method for providing an encapsulated pharmaceutical composition is discussed in published European patent Application No. 77,956, published May 4, 1983. EPO Publication No. 77,956 discloses the use of microcapsules containing a coated core material such as pharmaceutical compounds and foodstuffs. The coating is applied by dispersing the core material into a solution containing ethyl cellulose as the wall-forming material. A phase separation of the ethyl cellulose from the dispersion of core material is carried out by cooling the dispersion. During this cooling, an enteric polymer material is incorporated into the ethyl cellulose coating walls by adding the enteric polymer material with stirring while the ethyl cellulose is still in the "gel" state. The enteric polymer material thus added penetrates, and is dispersed into the coating walls. When the microcapsules are administered, the release of the active compound does not generally occur in the stomach. However, the enteric polymer material is easily dissolved in the intestinal tract, thereby making the microcapsules porous. The porosity of the microcapsules promotes the rapid release of the active compound in the intestinal tract.
A similar approach is found in Japanese Patent Publication No. 12614/81, published Mar. 23, 1981. Japanese Publication No. 12614/81 discloses an enteric protective coating composition which will not readily dissolve in acidic gastic juices, but rapidly (within minutes) dissolves at the pH found in the intestines. The enteric coating is an aqueous dispersion of, for example, hydroxy propyl methyl cellulose phthalate, a gelling agent such as diacetin, and hydroxy propyl methyl cellulose. See, also, Japanese Patent Publication No. 11687/81, published Mar. 16, 1981, which uses hydroxy propyl methyl cellulose phthalate as an enteric coating.
The systems described in the EPO and Japanese publications are essentially "delayed" release mechanisms. There is a delay of medicament release in the stomach, but once the coated medicament reaches the intestines, the release of medication is rapid. There is no sustained release of medication in the intestines.
The need thus remains for a sustained-release system which provides initial therapeutic levels of the drug; delays the delivery of another fraction of the drug to eliminate excess concentrations at 2-3 hours, and then, sustains the release of that delayed fraction to provide adequate drug levels for 8 or more hours.